A thermodynamic analysis of fibrillar polymorphism.

Abstract We explore the thermodynamic properties of three different fibrils of the peptide hormone glucagon, formed under different salt conditions (glycine, sulfate and NaCl, respectively), and differing considerably in compactness. The three fibrils display a large variation in the specific heat capacity Δ C p determined by isothermal titration calorimetry. Sulfate fibrils show a negative Δ C p expected from a folding reaction, while the Δ C p for glycine fibrils is essentially zero. NaCl fibrils, which are less stable than the other fibrils, have a large and positive ∆ C p . The predicted change in solvent accessible area is not a useful predictor of fibrillar Δ C p unlike the case for globular proteins. We speculate that strong backbone interactions may lead to the unfavorable burial of polar side residues, water and/or charged groups which all can have major influence on the change in ∆ C p . These results highlight differences in the driving forces of native folding and fibril formation.